Reports: UNI149471-UNI1: Aziridination and Retro-Aldol Fragmentation of Dioxenones: Application in the Synthesis of alpha-Amino Acids and 2-Benzazepine Derivatives

Currently, our research group is pursuing the
development of efficient methods to incorporate nitrogen into structurally
complex and somewhat unstable 1,3-dioxenones via direct aziridination. Our plan is to use nucleophilic ring
opening to manipulate the aziridine products into a variety of
non-proteinogenic amino acids. More
specifically, this project includes the simple construction of a variably
substituted b-ketoester, such as 1, that is covalently trapped in its enolic form as a
1,3-dioxen-4-one (2). The development of an aziridination
protocol for the dioxenones, then investigation of the retro-aldol
fragmentation of the resultant bicyclic structure will furnish an array of
substituted amino acids.

Numerous synthetic examples of aziridination are
reported in the chemical literature, however there are few reports of
aziridination of enol ethers, a,b-unsaturated esters and even fewer examples
involving both the enol and ester functionalities in the same molecule, such as
the 1,3-dioxen-4-one with which we are working. Known methods for the direct
aziridination of alkenes are limited by the substitution of the alkene itself
and the reactivity of the nitrogen equivalent. For example, many of these nitrogen equivalents
are utilized as a high-energy nitrene intermediates that are rapidly added to an
available alkene. The generation of
nitrenes can be achieved by photolysis or thermolysis of an azide, or the formation
of a metal-nitrene from iminoiodinanes, among other methods. Most of these methods are confined to
sterically available alkenes and yields are calculated on the equivalency of
the nitrene when using excess amount of the alkene substrate.

In this project, we have been directing most of our
energy on the aziridination of dixoenone and pyranone substrates (such as 2). This current progress of this work, for
the funding period of September 2010 to August 2011, is summarized below.

Summary
of Experimental Work:

During the second year of this research, we have continued
our investigation the direct aziridination of 2,2,6-trimethyl-1,3-dioxen-4-one
(4). We had elected to begin our studies with
dioxenone (4) due to its commercial
availability. Our trials began with
metal nitrene insertion to afford compound
5. Our initial result was
promising, however after an exhaustive examination of this reaction, we found
no possibility of reproducibility or acceptable yields using metal nitrenes
formed from iminoiodinanes. Three
different aryl iminoiodinanes were prepared, and a sampling of Rh2(OAc)4,
Cu(I) and Cu(II) catalysts were tested.
We also screened a number of conditions by changing both solvents and
temperature, yet we never observed the complete consumption of the dioxenone 4 and we were also unable to isolate
any appreciable amount of aziridine 5 that
we once observed in the 1H NMR of the reaction mixture.

In an effort to develop a more atom economical
approach to the aziridination, we
focused on employing ethylazidoformate as a nitrene
precursor to affect our desired aziridination. With precedent existing for nitrene
formation under photolytic or thermolytic conditions (no metal catalyst
required), we determined that aziridine 6
could be observed in about 30% conversion.

Using microwave irradiation, the reaction duration
was minimized to one hour (also avoiding some thermal decomposition) and we
were able to cleanly isolate and identify both products 6 and 7 of the reaction
of ethylazidoformate with dioxenone 4 in dichloromethane (DCM), albeit in
low yields. By changing the
reaction solvent to a higher boiling solvent, dichloroethane (DCE), we retained
the same results, but were unable to increase the yield of 6 in this transformation.
We would still like to
deduce the mechanistic pathway that accounts for the formation of carbamate
ester 7 in these reactions. If 7
is a secondary product from the ring opening of the aziridine, we may be able
to optimize the formation of 6 .

In addition to examining the reactivity of methyl-substituted
dioxenone 4, our research group planned
and synthesized two other dioxenone substrates with variable alkene
substitution for use in the aziridination studies. The first of the derivatives, 8, was designed to probe the reactivity
of a disubstituted alkene within the
dioxenone ring. We had hoped that
the pi system would be more sterically available to nitrene addition, however
with less substitution, the dioxenone was also more prone to cycloreversion.

The second substrate, 9, replaced the methyl group with and phenyl ring. This change allowed us to have the
stability of a trisubstituted alkene, but with different steric and electronic
demands on the pi system. Product 10 was formed in moderate yield and the
reaction showed little to no evidence of the aziridine opening or carbamate
ester product like 7. We are now in the process of tuning the
phenyl ring with both electron poor and electron rich substitutents to optimize
this reaction.

Concurrent with the work above, we prepared a
seemingly more stable, pyranone substrate (11)
to test our ethylazidoformate aziridination protocol. In just one aziridination attempt, the
analogue showed conversion to the desired aziridine product. Even though 12 will not allow us the facile retro-aldol fragmentation in our
original plan, we would like to optimize this result to include with our
aziridination studies.

Conclusion and Future Direction

The details of this work were presented at the
Local Mid-Hudson American Chemical Society Meeting on April 15th,
2011 at Bard College by undergraduates who have contributed to various aspects
of this project. These Bard
College undergraduates include – Madison Fletcher '12, Youseung Kim '12,
Nicole Camasso '12, and Nathan Steinauer '13. Prabarna Ganguly '13 and Xiaohan
Sun '13 also contributed to the synthesis of dioxenone derivatives.

This project has led to the development of a
research program concerning the dirhodium catalyzed intramolecular
aziridination to prepare both dihydroisoquinolones and dehydroisoindolone
scaffolds.

At this time we are in the process of reproducing
our current data, generating parallel examples, and testing variably substituted
dioxenones toward publication (with undergraduate coauthors) within the year.